This invention relates to novel aliphatic compounds, methods for producing them, and pharmaceuticals comprising the aliphatic compounds as an active ingredient.
Alpha granules released from activated platelets during the process of hemostasis contain serotonin, ADP and the aliphatic derivative, 2-amino-3-hydroxy-4-octadecene-1-phosphate (AHOP). Serotonin shows vasoconstriction, and ADP exhibits platelet aggregation, both compounds promoting hemostasis, whereas the role of AHOP has been unknown. In recent years, endothelial differentiation gene (Edg), an orphan receptor for which AHOP is an endogenous ligand, has been discovered. The possibility is being shown that the binding of AHOP and Edg acts in directions toward promotion of arteriosclerosis, such as hemodynamic aggravation or vascular smooth muscle growth, or in directions toward the progression of respiratory diseases.
The gene of Edg was cloned as an orphan receptor in 1990 [Edg-1 (JBC, ""90, 265, p. 9308)]. Then, Edg-3 (BBRC, ""96, 227, p. 608) and Edg-5 (AGR16/H218) (JCB, ""96, 135, p. 1071) were obtained as homologues of Edg-1, but their physiological roles remained unclear. In 1998, however, the possibility of AHOP being an endogenous ligand for Edg-1 was suggested (Science, ""98, 279, p. 1552), and then Edg-3 and Edg-5 were also shown to be AHOP-specific receptors (BBRC, ""99, 260, p. 263; JBC, ""99, 274, 27, p. 18997).
Edg-1 on the vascular endothelial cell, when stimulated by AHOP, upregulates an adhesion protein, such as cadherin, through activation of low molecular weight GTP-binding protein Rho (Science, ""98, 279, p. 1552). T lymphocyte-derived strain cells, upon stimulation by AHOP, accelerates vascular layer penetration in an in vitro pseudo-blood vessel model (EMBO J., ""98, vol. 17, No. 14, p.4066). Okajima et al. conducted pseudo-blood vessel migration tests using CHO cells forced to express Edg-1 or Edg-3, and found migration to be promoted AHOP concentration-dependently in either case (""99 Congress of the Japanese Biochemical Society, A collection of the Abstracts, p. 883). On the other hand, Igarashi et al. showed that the cancer cell strain F10 underwent suppression of migration by about a maximum of 80% concentration-dependently at an AHOP concentration of 10xe2x88x928 to 10xe2x88x926 M in a pseudo-blood vessel model, but Edg-1 or Edg-3 was scarcely expressed, and Edg-5 was expressed, in the F10 cells (""99 Congress of the Japanese Biochemical Society). In connection with these findings, the possibility was pointed out that AHOP showed the suppression of migration because of a difference in subspecies (""99 Congress of the Japanese Biochemical Society, A collection of the Abstracts, p. 675, p. 883).
AHOP-responsive activation of MAP kinase was observed in vascular smooth muscle cells (Eur. J. Biochem., ""98, 257, p. 403) or respiratory tract smooth muscle cells (Biochem. J., ""99, 338, p. 643), indicating the possibility for AHOP to act in a direction toward the growth of vascular smooth muscle cells.
Sugiyama et al. administered AHOP to rats by the caudal vein route, and observed hemodynamics. They noted significant drops in two parameters, systolic blood pressure and time differential of left ventricular pressure, showing the possibility that AHOP acts in a direction toward decline of cardiac function in vivo (A collection of the Abstracts at the ""00 Congress of the Japanese Pharmacological Society, p. 127).
The possibility is also pointed out that AHOP activates muscarinic receptor inward K+ rectifier to cause arrhythmia (""99 Pfugers Arch-Eur J Phisiol 438, pp. 642-648). Thus, an Edg receptor antagonist can be considered to have a possibility for taking effect against arrhythmia.
The effect of AHOP on vascular endothelial cells was studied in an angiogenic animal model. This study demonstrated that angiogenesis by a growth factor, such as VEGF or FGF-2, was synergistically promoted by AHOP bound to Edg-1 or Edg-3, thus showing the possibility that Edg acts on the progression of rheumatism, solid carcinoma, or diabetic retinopathy (Cell, ""99, p. 301).
The possibility has been presented that excessive inflammation or respiratory tract remodeling, caused by the binding of AHOP and Edg receptor, results in the progression of pneumonia, chronic obstructive airway disease, COPD) or respiratory hypertension (Pulmonary Pharmacology and Therapeutics, 2000, 13, p. 99).
Suramin, an agent for eradicating Protozoa Trypanosoma, is reported to show Edg-3-specific antagonism and inhibit a signal for binding of AHOP and Edg (J. B. C., ""99, 274, 27, p. 18997). Suramin is shown to be therapeutically effective in arteriosclerosis pathogenesis models (Circulation, ""99, Cardiovascular Res., ""94, 28, p. 1166), and Edg antagonism may be involved in the mechanism of this therapeutic effect.
Considered overall, these findings show the possibilities that AHOP bound to Edg acts in promoting arteriosclerosis, as evidenced by inflammatory cell activation, vascular smooth muscle cell growth or hemodynamic aggravation, and in promoting angiogenesis in favor of progression of rheumatism, solid carcinoma, or diabetic retinopathy. That is, substances antagonizing Edg are likely to show the properties of anti-cardiovascular diseases (for example, anti-arteriosclerosis, anti-cardiac diseases (e.g. anti-arrhythmia, anti-myocardial infarction)), anti-rheumatism, anti-cancer, anti-diabetic retinopathy, and anti-respiratory diseases.
The inventors of this invention performed in-depth studies in the light of the above circumstances, and newly discovered compounds represented by formulas (I) to (V) shown below. They found that these compounds (hereinafter referred to as xe2x80x9ccompounds of the present inventionxe2x80x9d) are antagonistic to Edg receptor. The present invention is based on this finding, and its object is to provide novel aliphatic compounds, methods for producing them, and pharmaceuticals comprising these compounds.
The present invention relates to an aliphatic compound represented by the following formula (I) 
where n denotes an integer of 1 to 11, and 1 denotes an integer of 1 to 16, which is an optical isomer of the (2R,3S,2xe2x80x2S) configuration when the 8-position is a double bond, or an optical isomer of the (2S,3R,2xe2x80x2RS) configuration when the 8-position is a single bond.
In the above formula, the wavy line refers to the inclusion of any of the optical isomerisms (R), (S) and racemic modification. Herein, the upper chain is called the first chain, and the lower chain is called the second chain.